Pantoprazole Compositions and Methods

ABSTRACT

A spray-dried storage stable pantoprazole composition is provided. The pantoprazole composition includes a pantoprazole and an excipient matrix including sodium chloride (NaCl). The pantoprazole is substantially uniformly dispersed in the excipient matrix. A method for forming a storage stable pantoprazole composition is also provided. The method includes combining a bulking agent and water to form a first solution, combining a pantoprazole and the first solution to form a second solution, combining sodium hydroxide and the second solution to form a bulk solution, and removing water from the bulk solution by drying to form the storage stable pantoprazole composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is U.S. Non-provisional Patent Application which claimspriority to U.S. Provisional Patent Application No. 63/070,510, filedAug. 26, 2020, which is hereby incorporated in its entirety byreference.

FIELD OF THE INVENTION

The field of the invention is a ready-to-use (RTU) pantoprazole sodiumcomposition for injection, and especially a stable composition in aneasy-to-use system for administration.

BACKGROUND

The following description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed invention, or that any publication specifically orimplicitly referenced is prior art.

All publications identified herein are incorporated by reference to thesame extent as if each individual publication or patent application werespecifically and individually indicated to be incorporated by reference.Where a definition or use of a term in an incorporated reference isinconsistent or contrary to the definition of that term provided herein,the definition of that term provided herein applies and the definitionof that term in the reference does not apply.

Pantoprazole is a medication used for the treatment of stomach ulcers,short-term treatment of erosive esophagitis due to gastroesophagealreflux disease (GERD), maintenance of healing of erosive esophagitis,and pathological hypersecretory conditions including Zollinger-Ellisonsyndrome. It may also be used along with other medications to eliminateHelicobacter pylori. Effectiveness is similar to other proton pumpinhibitors (PPIs). It is available as a solid for oral administrationand as an injectable for intravenous (I.V.) administration.

The stability of the pantoprazole compound in aqueous solution ispH-dependent with the rate of degradation increasing with decreasing pH.The reconstituted solution of PROTONIX I.V. for injection (WyethPharmaceuticals LLC) is in the pH range 9.0 to 10.5. PROTONIX I.V. issupplied for intravenous administration as a sterile, freeze-driedpowder in a single-dose clear glass vial fitted with a rubber stopperand crimp seal. Each vial contains 40 mg pantoprazole (equivalent to45.1 mg of pantoprazole sodium), edetate disodium (1 mg), and sodiumhydroxide to adjust pH.

The reconstituted solution of Pantoprazole Sodium for Injection is inthe pH range 9.5 to 11.5. Pantoprazole Sodium for injection (HikmaPharmaceuticals LLC) is supplied for intravenous administration as asterile lyophilized powder in a single-dose clear glass vial fitted witha rubber stopper and crimp seal. Each vial contains 40 mg pantoprazole(equivalent to 45.1 mg of pantoprazole sodium), and sodium hydroxide toadjust pH.

However, storage of the pantoprazole powder in glass vials exposes thepantoprazole sodium to light which increases degradation of thecomposition. Furthermore, the preparation of an injectable solutionusing a stoppered glass vial is often contaminated, making thepreparation of an aseptic intravenous solution of pantoprazole sodiumtime consuming and costly.

Solutions of pantoprazole including saline solution have beenrefrigerated for up to 28 days at 2° C. to 8° C. See, e.g., Donnelly,2011, Can J Hosp Pharm. 2011 May; 64(3):192-8. However, refrigeration isnot always available or practical and the solutions still suffer frominaccurate dosing due to the use of conventional reconstitutedpantoprazole sodium for injection (Sandoz Canada Inc, Boucherville,Quebec).

Furthermore, because pantoprazole is hydrolytically labile, it must belyophilized to ensure shelf-life stability. Considering the lower (e.g.,milligrams) amounts of pantoprazole in a single dosage (e.g., 40 mg or80 mg), additional excipients (e.g., bulking agents) are necessary torender the lyophilization process effective. See, e.g., Baheti et al.,2010, J. Excipients and Food Chem., 1: 41-54. The pantoprazole activeingredient must remain sterile and homogenous for safe and effectiveadministration to the patient; however, selection of bulking agents andlyophilization processes can impart increased variability and cost.

Thus, there is still a need for a ready-to-use (RTU) sterilepantoprazole powder that is stably stored and easily reconstituted whilemaintaining sterility to form an aseptic intravenous pantoprazole sodiumpreparation that can be cost effectively manufactured.

SUMMARY OF THE INVENTION

The inventors have advantageously contemplated a composition of astabilized pantoprazole sodium blend made of pantoprazole present at 40mg or 80 mg or a batch multiple thereof and a bulking agent, wherein thestabilized pantoprazole blend is a spray dried powder blend having nomore than 0.20% pantoprazole sulfone degradant.

The contemplated bulking agent in the stabilized pantoprazole sodiumblend may be a salt, an amino acid, a sugar, or a combination thereof.More specifically, the salt may be selected from sodium chloride (NaCl),magnesium chloride (MgCl₂), or calcium chloride (CaCl₂), the amino acidmay be glycine, and the sugar may be dextrose, sucrose, or trehalose.Preferably the bulking agent is NaCl. More preferably, the bulking agentis NaCl present at about 800 mg to 1 gram for each 40 mg or 80 mg doseof the pantoprazole. Most preferably, the bulking agent is NaCl at about900 mg for each 40 mg or 80 mg dose of the pantoprazole.

The contemplated stabilized pantoprazole sodium blend composition mayinclude NaOH at about 3 to 4 mg for each 40 mg or 80 mg dose of thepantoprazole.

In preferred embodiments, the stabilized pantoprazole sodium blend hasno more than 0.30% pantoprazole sulfone degradant at a storagetemperature up to about 25° C. In more preferred embodiments, thestabilized pantoprazole sodium blend has no more than 0.20% pantoprazolesulfone degradant at a storage temperature up to about 25° C.

In some embodiments, the contemplated method of making a stabilizedpantoprazole sodium blend powder as disclosed includes deionized water.Preferably, the water is at a volume of about 80 ml for each 40 mg or 80mg dose of the pantoprazole.

In further embodiments, the bulking agent added in the method of makingthe stabilized pantoprazole sodium blend powder is a salt, an aminoacid, a sugar, or combination thereof. Preferably the salt is sodiumchloride (NaCl), magnesium chloride (MgCl2), or calcium chloride(CaCl2); the amino acid is glycine; and the sugar is dextrose, sucrose,or trehalose. In more preferred embodiments, the bulking agent is NaCl.Most preferably, 900 mg of NaCl is added for each 40 mg or 80 mg dose ofthe pantoprazole to the first solution as disclosed.

In still further embodiments, the azeotropic agent added in the methodof making the stabilized pantoprazole sodium blend powder isacetonitrile solution. Preferably, about 40 to 60 ml of acetonitrilesolution are added for each 40 mg or 80 mg dose of the pantoprazole tothe third solution as disclosed herein.

In additional embodiments, the third solution is filtered prior to theaddition of the azeotropic agent.

In still other embodiments, the spray drying step of the contemplatedmethod includes a set of parameters that are implemented in the spraydrying process by the spray dryer, wherein the set of parameters includean inlet temperature of 120 to 220° C., an outlet temperature of 60 to90° C., a flow rate of about 30 to 65 mm, and a feed rate of about 20 to40%. Preferably, the set of parameters that are implemented in the spraydrying process by the spray dryer include an inlet temperature of 145 to180° C., an outlet temperature of 86 to 89° C., a flow rate of about 65mm, and a feed rate of about 20 to 40%.

Notably, the inventors have contemplated a method of making aready-to-use (RTU) pantoprazole sodium for injection in which thedisclosed method of making the stabilized pantoprazole sodium blendpowder additionally includes aseptically providing the stabilizedpantoprazole sodium blend powder to a first pouch of a flexiblecontainer and sealing the first pouch with the stabilized pantoprazolesodium blend powder therein, and aseptically providing sterile water toa second pouch of the flexible container and sealing the second pouchwith the sterile water therein, wherein the flexible container comprisesthe first and second pouches as two sealable compartments adjacent toeach other having a frangible seal therebetween. Preferably, the sealingof the first and second pouches is carried in the presence of nitrogengas. Also, the flexible container is preferably made of or includesaluminum.

Considered from a different perspective, the inventors have alsocontemplated a system for forming and administering a ready-to-use (RTU)pantoprazole sodium solution for injection, in which the system includesa flexible container having two sealed compartments including a firstpouch and a second pouch, wherein the two sealed compartments areadjacent to each other having a frangible seal therebetween. In thisflexible container system, the stabilized pantoprazole sodium blendpowder composition as disclosed herein is provided and sealed within thefirst pouch, and sterile water is provided and sealed within the secondpouch, wherein the stabilized pantoprazole sodium blend powder has nomore than 0.20% pantoprazole sulfone degradant. As disclosed herein, thestabilized pantoprazole sodium blend powder composition includespantoprazole, sodium hydroxide, and a bulking agent.

In additional embodiments, the flexible container of the disclosedsystem has a vertical orientation in which the first pouch is alignedbeneath the second pouch with the frangible seal forming both a topmostside of the first pouch and a bottommost side of the second pouch.

In preferred embodiments, 40 mg or 80 mg of the pantoprazole is presentin the ready-to-use (RTU) pantoprazole sodium solution for injection. Inother preferred embodiments, the sodium hydroxide is present in anamount of about 2 to 5 mg. More preferably, the sodium hydroxide ispresent in an amount of about 3 to 4 mg.

In still other embodiments, the bulking agent in the stabilizedpantoprazole sodium blend powder composition of the contemplated systemis a salt, an amino acid, a sugar, or a combination thereof. Preferablythe salt is sodium chloride (NaCl), magnesium chloride (MgCl₂), orcalcium chloride (CaCl₂); the amino acid is glycine; and the sugar isdextrose, sucrose, or trehalose. In more preferred embodiments, thebulking agent in the stabilized pantoprazole sodium blend powdercomposition of the contemplated system is NaCl. Most preferably, NaCl ispresent at about 900 mg.

In additional embodiments, the flexible container of the contemplatedsystem includes or is made of aluminum. The first pouch of the flexiblecontainer may be or may be made from an opaque material. The secondpouch may include a transparent material.

In some embodiments, the forming of the RTU pantoprazole sodium solutionincludes breaking the frangible seal between the first pouch and thesecond pouch, thereby allowing the sterile water to combine with thestabilized pantoprazole sodium blend powder in the first pouch tothereby form the RTU pantoprazole sodium solution.

The system for forming and administering the RTU pantoprazole sodiumsolution may also include a flexible conduit coupled to the first pouch,wherein the flexible conduit is in fluid communication with the firstpouch for administering the RTU pantoprazole sodium solution out of thefirst pouch. Preferably, administering the RTU pantoprazole sodiumsolution out of the first pouch includes administering the RTUpantoprazole sodium solution intravenously to a subject.

Various objects, features, aspects and advantages of the inventivesubject matter will become more apparent from the following detaileddescription of preferred embodiments, along with the accompanyingdrawing figures in which like numerals represent like components.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photo of a flexible container 10 with two sealedcompartments 20, 30 adjacent to each other having a frangible seal 40therebetween, according to embodiments of the present invention.

FIG. 2 is a schematic of a flexible container 10 with two sealedcompartments 20, 30 adjacent to each other having a frangible seal 40therebetween, according to embodiments of the present invention.

FIGS. 3 and 4 are flow charts of the contemplated method as disclosedherein according to embodiments of the present invention.

DETAILED DESCRIPTION

The inventors have advantageously contemplated a composition of spraydried pantoprazole sodium for injection made of a few components thatcan be sterilely and stably stored as well as reconstituted in a pouchcontainer which is easily connected for administration to a patient byinjection.

Ideally, a medicinal formulation of pantoprazole is as simple (e.g.,pure, having few additional ingredients) as possible. However, given thecharacteristics of the pantoprazole molecule, additives are necessaryfor manufacture as well as stability during storage. The pantoprazolehas the chemical name5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazoleand is a chiral compound. As utilized herein, the term pantoprazoleincludes the pure enantiomers of pantoprazole and their mixtures in anymixing ratio. (S)-pantoprazole [(−)-pantoprazole] may be mentioned byway of example. Pantoprazole is present here as such or in the form ofits salt with a base. Examples of salts with a base which may bementioned are sodium, potassium, magnesium and calcium salts.Pantoprazole and/or a salt thereof may contain various amounts ofsolvent when isolated in crystalline form. In connection with theinvention pantoprazole also refers to all solvates and in particular tohydrates of5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazoleand salts thereof. In certain embodiments, the pantoprazole includespantoprazole sodium sesquihydrate.

Lyophilization is a commonly used process for preparing thehydrolytically labile pantoprazole sodium for storage prior to use.Typically, the lyophilized pantoprazole sodium is reconstituted insolution prior to use—e.g., injection into the patient. Because thedosage of the pantoprazole sodium is milligram quantities,lyophilization of a single dose alone is ineffective, requiring theaddition of a bulking agent. Bulking agents that improve thelyophilization process also increase the manufacturing cost and canaffect the stability and effectiveness of the pantoprazole activeingredient. While freeze drying of pantoprazole has been previouslycarried out using various bulking agents, the inventors have discoveredthat using a spray drying technique for pantoprazole in the presence ofa bulking agent (e.g., sodium chloride (NaCl)) renders a highly stablepantoprazole sodium blend powder made from few components. Inparticular, the use of sodium chloride as the bulking agent for additionto and spray drying of the pantoprazole composition renders a moreeffective drying process than freeze drying or lyophilization.

In certain embodiments, the inventors contemplate a spray-dried storagestable pantoprazole composition include a pantoprazole and an excipientmatrix comprising sodium chloride with the pantoprazole substantiallyuniformly dispersed in the excipient matrix. The phrase “substantiallyuniformly dispersed” with reference to the “excipient matrix” means thatany first portion of the composition includes pantoprazole in a firstamount relative to the weight of the first position, any second portionof the composition different than the first portion includespantoprazole in a second amount relative to the weight of the secondposition, and the amounts of the first portion and the second portionare within 10%, 5%, 3%, 2%, or 1% of each other. It is to be appreciatedthat during the process of forming the pantoprazole composition, thesodium chloride may be included as part of the bulking agent. Uponformation of the pantoprazole composition, the same sodium chloride maybe part of the excipient matrix by which the pantoprazole issubstantially uniformly dispersed therein. It has been surprisinglyfound that substantial uniform dispersion of the pantoprazole in theexcipient matrix including sodium chloride can be achieved byspray-drying. Further, it is contemplated that the forming thepantoprazole composition including sodium chloride by spray-dryingresults in a storage stable composition. Methods for forming thepantoprazole composition, along with kits including the pantoprazolecomposition, are also provided herein.

Without being bound by theory, inventors contemplate that spray-dryingcan effectively reduce the particle size of the pantoprazole. Thisreduced particle size can lead to improved blending with the bulkingagent thereby leading to improved accuracy of dosing of the pantoprazoleas compared to compositions formed using conventional drying methods(e.g. freeze drying or lyophilization). Specifically, as well known inthe art, freeze drying and lyophilization rely on a low temperaturedehydration process after freezing of the conventional pantoprazolecomposition to remove water at an interface of the conventionalpantoprazole composition exposed to the environment. As this processprogresses, the interface continues to move through the conventionalpantoprazole composition thereby exposing its pantoprazole to theinterface and environment. This exposure can lead to degradation of itspantoprazole. Beyond stability, spray-drying can improve dissolutionkinetics of the pantoprazole as compared to conventional drying methods(e.g. freeze drying or lyophilization) due to the decrease in particlesize of the pantoprazole.

Furthermore, the pantoprazole composition, after storage, exhibitsminimal formation of degradants. It is contemplated herein that theminimization of the formation of degradants is at least due tospray-drying and the excipient matrix including sodium chloride. Asdescribed above, the bulking agent including sodium chloride improvesuniformity of the dispersion of the pantoprazole in the excipientmatrix. In addition, without being bound by theory, the excipient matrixincluding at least the same sodium chloride may improve storagestability of the pantoprazole as compared to compositions free of sodiumchloride. In contrast to the inventive compositions described herein,conventional methods rely on refrigeration of aqueous compositionsincluding pantoprazole that results in inadequate storage stability. Asdescribed in greater detail below, the spray-dried storage stablepantoprazole composition can be stored in dry form (e.g. powder form) atelevated temperatures while still maintaining improved accuracy ofdosing of the pantoprazole.

In various embodiments, the composition, after storage at 25° C. and 40%relative humidity for 12 weeks, contains equal or less than 0.20%, equalor less than 0.15%, or equal or less than 0.10%, by weight of apantoprazole sulfone degradant based on a total weight of thecomposition. In these and other embodiments, the composition, afterstorage at 25° C. and 40% relative humidity for 12 weeks, contains equalor less than 1%, equal or less than 0.75%, or equal or less than 0.50%,by weight of total impurities (e.g. degradants) based on a total weightof the composition. Non-limiting example of contemplated impurities ofpantoprazole are shown in Table 1.

TABLE 1 Impurities of Pantoprazole Type of Name of Impurity Chemicalname Impurity Related Compound-A5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl) Degradant(Pantoprazole sulfone) methyl] sulphonyl)]-lH-benzimidazole Relatedcompound-B 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl) Process(Pantoprazole sulfide) methyl]thio]-lH-benzimidazole Related Compound-C5-(difluoromethoxy)-1H-benzimidazole-2-thiol Process (Benzimidazolethiolderivative) Related Compound-D 5-(difluoromethoxy)-2-[(RS)-[(3,4-Degradant (N1-Methyl dimethoxypyridin-2-yl)methyl] Sulfinyl]-1-methyl-pantoprazole) lH-benzimidazole Related Compound-F6-(difluoromethoxy)-2-[((RS)-[(3,4- Degradant (N3-dimethoxypyridin-2-yl)methyl] Sulfinyl]-1-methyl- Methylpantoprazole)lH-benzimidazole Related Compound-E Mixture of the stereoisomers of6,6′-bis (Difluoro- Process (Pantoprazole dimer)methoxy)-2,2′-bis[[(3,4-dimethoxypyridin-2yl) methyl]sulfinyl]-lH,l′H-5,5′-bibenzimidazolyl

In addition to sodium chloride, the excipient matrix may include a saltdifferent than sodium chloride, an amino acid, a sugar, or combinationsthereof. The salt different than sodium chloride may include magnesiumchloride (MgCl₂), calcium chloride (CaCl₂), or a combination thereof.The amino acid may include glycine. The sugar may include dextrose,sucrose, trehalose, or combinations thereof. In certain embodiments, theexcipient matrix consists essentially of, or consists of, NaCl. It is tobe appreciated that other components, such as pH modifiers (e.g. sodiumhydroxide (NaOH)), are not excipients of the excipient matrix. Invarious embodiments, the pantoprazole and the sodium chloride arepresent in the composition in a weight ratio of from about 1:100 toabout 1:1, from about 1:50 to about 1:5, or from about 1:20 to about1:10.

As introduced above and shown in FIGS. 1 and 2, the inventors havecontemplated a kit including the storage stable pantoprazole compositionand a liquid phase, along with a method of making the same. The kit(e.g. including a flexible container 10) may be a ready-to-use (RTU)pantoprazole sodium for injection including aseptically providing thestabilized pantoprazole sodium blend powder to a first chamber of afirst pouch 20 and sealing the first pouch 20 with the pantoprazolecomposition therein, and aseptically providing sterile water as theliquid phase to a second chamber of a second pouch 30 and sealing thesecond pouch 30 with the sterile water therein. In various embodiments,the flexible container 10 includes the first pouch 20 and the secondpouch 30 with the first and second chambers as two sealable chambersadjacent to each other having a frangible seal 40 therebetween. Incertain embodiments, the sealing of the first and second chambers iscarried in the presence of nitrogen gas. The flexible container may bemade of or includes a polymeric material including aluminum.

View from another perspective, the storage stable pantoprazolecomposition may be contained in the first chamber of the first pouch 20including the polymeric material. The storage stable pantoprazolecomposition may be present in the first chamber in an amount of fromabout 20 to about 100 mg, from about 30 mg to about 90 mg, or from about40 mg to about 80 mg. The liquid phase may be contained in the secondchamber of the second pouch 30 including the polymeric material. Incertain embodiments, the liquid phase comprises water. The liquid phasemay be present in the second chamber in an amount of from about 10 toabout 200 mL. In various embodiments, the first pouch 20 and the secondpouch 30 are coupled together and the first chamber and the secondchamber are isolated from each other.

In additional embodiments, the flexible container 10 has a verticalorientation in which the first pouch 20 is aligned beneath the secondpouch 30 with the frangible seal 40 forming both a topmost side of thefirst pouch 20 and a bottommost side of the second pouch 30. Thisorientation allows for the reconstituted solution of the storage stablepantoprazole composition in the lower (bottom) first pouch 20 with thewater from the second pouch 30 to be administered from the lower firstpouch 20 through a flexible conduit or tubing to an intravenous needleor port into the patient. For example, the flexible container 10 may beattached to a pole (e.g. an I.V. pole) and then the reconstitutedpantoprazole composition can be administered from the first pouch 20 tothe patient. In exemplary embodiments, 40 mg or 80 mg of thepantoprazole composition or a batch multiple thereof is present in aready-to-use (RTU) reconstituted pantoprazole solution for injection. Inother embodiments, the sodium hydroxide is present in an amount of about2 to 5 mg for each 40 mg or 80 mg dose of the pantoprazole. In certainembodiments, the sodium hydroxide is present in an amount of about 3 to4 mg for each 40 mg or 80 mg dose of the pantoprazole.

In additional embodiments, the flexible container 10 includes or is madeof a polymeric material including aluminum to protect and maintainstability of the pantoprazole composition. The first pouch 20 of theflexible container 10 may be or may be made from an opaque material toblock light from reaching the pantoprazole. Additionally, the secondpouch 30 may include a transparent material such that the sterile watertherein can be visually monitored for contaminants prior toreconstitution and use.

As would be readily understood by the skilled person, the forming of theRTU pantoprazole solution includes breaking the frangible seal 40between the first pouch 20 and the second pouch 30, thereby allowing thesterile water to combine with the storage stable pantoprazolecomposition in the first pouch 20 to thereby form the RTU pantoprazolesolution.

The system for forming and administering the RTU pantoprazole solutionmay also include a flexible conduit coupled to the first pouch 20,wherein the flexible conduit is in fluid communication with the firstpouch 20 for administering the RTU pantoprazole solution out of thefirst pouch 20. In various embodiments, administering the RTUpantoprazole solution out of the first pouch 20 includes administeringthe RTU pantoprazole solution intravenously to a subject.

A method for forming the storage stable pantoprazole compositionincludes combining a bulking agent and water to form a first solutionand combining the pantoprazole and the first solution to form a secondsolution. The first and second solutions may be formed at a temperatureof from about 1° C. to about 40° C. In particular, in one embodimentfrom about 1° C. to about 10° C. and in another embodiment from about15° C. to about 30° C. The first and second solutions may be formed inthe presence of an inert gas, such as nitrogen. The first and secondsolutions may be formed under agitation, such as mixing, for a period oftime sufficient to form the solution (e.g. at least 1 minute, at least 5minute, at least 30 minutes, at least 60 minutes, at least 120 minutes,240 minutes, or at least 24 hours). The bulking agent may include asalt, an amino acid, a sugar, or combinations thereof. The salt mayinclude sodium chloride (NaCl), magnesium chloride (MgCl₂), calciumchloride (CaCl₂), or combinations thereof. The amino acid may includeglycine. The sugar may include dextrose, sucrose, trehalose, orcombinations thereof. In various embodiments, the pantoprazole and thebulking agent (e.g. sodium chloride) are present in the second solutionin a weight ratio of from about 1:100 to about 1:1, from about 1:50 toabout 1:5, or from about 1:20 to about 1:10.

The method further includes combining a pH modifier (e.g. sodiumhydroxide) and the second solution to form a bulk solution. The pHmodifier is combined with the second solution in an amount sufficientfor the bulk solution to have a pH of from about 8 to about 10. The bulksolution may be formed at a temperature of from about 1° C. to about 40°C. In particular, in one embodiment from about 1° C. to about 10° C. andin another embodiment from about 15° C. to about 30° C. The bulksolution may be formed in the presence of an inert gas, such asnitrogen. The bulk solution may be formed under agitation, such asmixing, for a period of time sufficient to form the solution (e.g. atleast 1 minute, at least 5 minute, at least 30 minutes, at least 60minutes, at least 120 minutes, 240 minutes, or at least 24 hours).

The method further includes removing water from the bulk solution bydrying to form the storage stable pantoprazole composition. The step ofremoving the water from the bulk solution by drying includesspray-drying, spray solidification, spray pilling, or combinationsthereof. In certain embodiments, spray-drying is utilized to dry thestorage stable pantoprazole composition.

Spray-drying may be carried out using any method know in the artsuitable for drying the storage stable pantoprazole composition.Suitable methods can be found in K. Masters, Spray Drying Handbook, 5thEd. 1991, and J. Broadhead, S. K. Edmond Ronan, C. T. Rhodes, The SprayDrying of Pharmaceuticals, Drug Dev. Ind. Pharm. 18, 1169 (1992). Theprocess of spray-drying includes dispersing a solution or suspension ofthe product to be dried into fine droplets and drying it with a hotstream of gas. The solid component remaining after evaporation of thesolvent is removed from the stream of gas by a cyclone and/or by afilter unit and collected.

Spray drying may include a set of parameters that are implemented in thespray drying process by the spray dryer, wherein the set of parametersinclude an inlet temperature of 120 to 220° C., an outlet temperature of60 to 90° C., a flow rate (e.g., Q-flow) of about 30 to 65 mm, and afeed rate of about 20 to 40%. Preferably, the set of parameters that areimplemented in the spray drying process by the spray dryer include aninlet temperature of 145 to 180° C., an outlet temperature of 86 to 89°C., a flow rate of about 65 mm, and a feed rate of about 20 to 40%.

In other embodiments, the step of combining the pH modifier (e.g. sodiumhydroxide) and the second solution is further defined as forming a thirdsolution, and wherein the method further includes combining a solventand the third solution to form the bulk solution. In these embodiments,the third and bulk solutions may be formed at a temperature of fromabout 1° C. to about 40° C. In particular, in one embodiment from about1° C. to about 10° C. and in another embodiment from about 15° C. toabout 30° C. The third and bulk solutions may be formed in the presenceof an inert gas, such as nitrogen. The third and bulk solutions may beformed under agitation, such as mixing, for a period of time sufficientto form the solution (e.g. at least 1 minute, at least 5 minute, atleast 30 minutes, at least 60 minutes, at least 120 minutes, 240minutes, or at least 24 hours). In various embodiments, the solventcomprises acetone.

In various embodiments, the solvent may include an azeotropic agent,such as an acetonitrile solution. In one embodiment, about 40 to about60 ml of acetonitrile solution is added to the third solution asdisclosed herein. An azeotropic agent like acetonitrile is added toensure that the entire pantoprazole blend is processed through the spraydryer homogenously as one mixture having one boiling point, as opposedto being processed based on the boiling point of each component in theblend. In additional embodiments, to ensure undissolved particles areremoved, the third solution is filtered prior to the addition of theazeotropic agent.

In additional embodiments, the contemplated method includes providingand processing a solution of water and the azeotropic agent through thespray dryer prior to providing the pantoprazole sodium blend solution tothe spray dryer. Flushing the spray dryer with the blank solution of thepantoprazole sodium blend further aides in spraying drying a homogenousand uniform powder product of pantoprazole sodium including sodiumhydroxide and the bulking agent. Preferably, the azeotropic agent isacetonitrile.

EXAMPLES

Exemplary spray-dried storage stable pantoprazole compositions wereformed including the components as set forth in Formulations 1A, 1B, and2 in Table 2A and 3A below using the parameters as set forth in Tables2B and 3B based on Blending Processes I and II described below (seeFIGS. 3 and 4). The bulk solutions prior to spray drying were formedunder the following condition:

-   -   Ex. Comp. 1, 7, 13, and 19—Bulk solutions prepared at 25° C. and        then spray dried.    -   Ex. Comp. 2, 8, 14, and 20—Bulk solutions prepared at 25° C. and        then spray dried.    -   Ex. Comp. 3, 9, 15, and 21—Bulk solutions prepared at 4° C. and        then spray dried.    -   Ex. Comp. 4, 10, 16, and 22—Bulk solutions prepared at 4° C. and        then spray dried. The powdered pantoprazole compositions after        spray drying were then exposed to 30° C./65% Rh for 7.30 hours.    -   Ex. Comp. 5, 11, 17, and 23—Bulk solutions prepared at 4° C.        with 50% less NaCl and then spray dried.    -   Ex. Comp. 6, 12, 18, and 24—Bulk solution prepared in water and        acetone and spray dried.

For Blending Process I, a bulk solution was formed according to Table3A. Water at a temperature of 4° C. was combined with sodium chlorideand stirred until the sodium chloride was dissolved to form a firstsolution. Pantoprazole sodium sesquihydrate was combined with the firstsolution and stirred until the pantoprazole sodium sesquihydrate wasdissolved to form a second solution. Sodium hydroxide was combined withthe second solution and stirred until the sodium hydroxide was dissolvedto form a bulk solution having the desired pH. The bulk solution wasthen filtered through a 0.2μ PES filter. The filtered bulk solution wasthen spray-dried according to Table 2B to form the exemplary spray-driedstorage stable pantoprazole compositions.

For Blending Process II, a bulk solution was formed according to Table3B. Water at a temperature of 4° C. was combined with sodium chlorideand stirred until the sodium chloride was dissolved to form a firstsolution. Pantoprazole sodium sesquihydrate was combined with the firstsolution and stirred until the pantoprazole sodium sesquihydrate was atleast partially dissolved to form a second solution (heavy solution).Sodium hydroxide was combined with the second solution and stirred untilthe sodium hydroxide was dissolved to form a third solution having thedesired pH. Acetone was combined with the third solution to form a bulksolution. The bulk solution was then filtered through a 0.2μ PES filter.The filtered bulk solution was then spray-dried according to 3B to formthe exemplary spray-dried storage stable pantoprazole compositions.

After spray-dry, each of the exemplary spray-dried storage stablepantoprazole compositions was filled in a duplex IV bag. One chamber ofeach bag filled with spray dry powder containing 40 mg of thepantoprazole composition and sealed with a hand sealer. Another chamberwas filled with water and closed with a twist off port. There were twobags for each stability station. The bags were stored at variousconditions for stability testing

At each evaluation time point, one bag was directly admixed with thewater and the resulting solution was evaluated (“Analysis ofPantoprazole Composition without Liquid Phase”) while another bag wasevaluated as a powder without the water (“Analysis of PantoprazoleComposition combined with Liquid Phase”). The results of the evaluationsfor storage stability for a period of 3 months under various processingand storage conditions are shown in Tables 4A-C, 5A-C, 6A-C, and 7A-C.

In view of the evaluations, the exemplary spray-dried storage stablepantoprazole compositions contain equal or less than 0.20% by weight ofa pantoprazole sulfone degradant based on a total weight of thecompositions and contain equal or less than 1% by weight of totalimpurities based on a total weight of the compositions after 2 months ofstability testing. Further a majority of the exemplary spray-driedstorage stable pantoprazole compositions exhibit excellent storagestability after 3 months of stability testing.

TABLE 2A Bulk Solution Formulation IA and IB Exemplary FormulationFormulation Component Ingredient 1A Amount 1B Amount Vehicle Water 800mL 800 mL Bulking Agent NaCl 36.0 grams 18.0 grams PantoprazolePantoprazole Sodium 1.8 grams 1.8 grams Sesquihydrate pH Modifier NaOH34.0 grams 34.0 grams

Pantoprazole sodium sesquihydrate was from MSN Laboratories Pvt. Ltd.,API molecular formula: C₁₆H₁₄F₂N₃Na0₄S, 1.5 H₂0, chemical name:1H-Benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-sodium salt, sesquihydrate.

Sodium chloride (NaCl) is commercially available from Avantor-J.T.Baker.

Sodium hydroxide (NaOH) is commercially available from Sigma Aldrich.

TABLE 2B Spray-Drying Parameters I Parameters Conditions InstrumentsBuchi Instrument B-290 + Dehumidifier B-296, Open Mode Cyclone StandardAspirator 100% Q-Flow 40 mm Pump 10% Inlet Temp 155-170° C. Outlet Temp104-108° C. Spray Gas Nitrogen Outlet Filter Polyester Feed TubingSilicone Nozzle Two Fluid

TABLE 3A Bulk Solution Formulation II Component Exemplary IngredientFormulation II Amount Vehicle Water 350 milliliters Bulking Agent NaCl36.0 grams Pantoprazole Pantoprazole Sodium 1.8 grams Sesquihydrate pHModifier NaOH 34.0 grams Solvent Acetone 500 milliliters

Pantoprazole sodium sesquihydrate was from MSN Laboratories Pvt. Ltd.,API molecular formula: C₁₆H₁₄F₂N₃Na0₄S, 1.5 H₂0, chemical name:1H-Benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-sodium salt, sesquihydrate.

Sodium chloride (NaCl) is commercially available from Avantor-J.T.Baker.

Sodium hydroxide (NaOH) is commercially available from Sigma Aldrich.

Acetone is commercially available.

TABLE 3B Spray-Drying Parameters II Parameters Conditions InstrumentsBuchi Instrument B-290 + Dehumidifier B-296 + Inert Loop B-295, ClosedMode Cyclone Standard Aspirator 100% Q-Flow 40 mm Pump 10% Inlet Temp85-95° C. Outlet Temp 65-70° C. Spray Gas Nitrogen Outlet FilterPolyester Feed Tubing Tygon MH 2375 Nozzle Two Fluid

TABLE 4A Stability Testing at 2-8° C. of Pantoprazole Compositionsformed from Bulk Solutions Processed under Various Conditions ExemplaryComposition 1 Exemplary Composition 2 Bulk Solution Formulation IA IABlending Process Process I Process I Bulk Solution Temperature 25° C.25° C. Condition 1 Month 3 Months 1 Month 3 Months Initial 2-8° C. 2-8°C. Initial 2-8° C. 2-8° C. Analysis of Pantoprazole Composition withoutLiquid Phase Description White White White White White White coloredcolored colored colored colored colored powder powder powder powderpowder powder Water content 0.500 0.555 0.545 0.555 0.705 0.590 Assay -Pantoprazole 99.2 95.7 95.1 99.2 99.4 93.0 RS Imp A 0.07 0.06 0.07 0.070.07 0.07 Imp B ND ND ND ND ND ND Imp D&F 0.06 0.06 0.10 0.06 0.14 0.12Imp E 0.01 0.02 0.01 0.01 ND 0.01 SMI 0.03 0.02 0.02 0.03 0.04 0.02 ImpC 0.01 0.00 0.02 0.01 ND 0.02 Total (Excluding 0.24 0.26 0.26 0.24 0.250.27 Imp C) Analysis of Pantoprazole Composition combined with LiquidPhase Description Clear Clear Clear Clear Clear Clear ColorlessColorless Colorless Colorless Colorless Colorless Solution SolutionSolution Solution Solution Solution pH 9.58 9.44 9.51 9.58 9.47 9.49Osmolality 279 280 296 273 276 293 Assay - Pantoprazole NA 100.9 99.9 NANA 98.6 Assay - NaCl 99.8 98.5 100.8 99.3 102.2 100.4 RS Imp A NA 0.080.08 NA 0.07 0.07 Imp B NA ND ND NA ND ND Imp D&F NA 0.10 0.14 NA 0.110.15 Imp E NA 0.01 0.01 NA 0.01 0.01 SMI NA 0.07 0.08 NA 0.07 0.05 Imp CNA 0.02 0.03 NA 0.03 0.02 Total (Excluding NA 0.36 0.44 NA 0.35 0.39 ImpC) LPC TEST 10 μm NA Complies Complies NA Complies Complies 1A 25 μm NANA

TABLE 4B Stability Testing at 2-8° C. of Pantoprazole Compositionsformed from Bulk Solutions Processed under Various Conditions (cont.)Exemplary Composition 3 Exemplary Composition 4 Bulk SolutionFormulation IA IA Blending Process Process I Process I Bulk SolutionTemperature 4° C. 4° C., Exposed to 30/65 for 7.30 hr Condition 1 Month3 Months 1 Month 3 Months Initial 2-8° C. 2-8° C. Initial 2-8° C. 2-8°C. Analysis of Pantoprazole Composition without Liquid Phase DescriptionWhite White White White White White colored colored colored coloredcolored colored powder powder powder powder powder powder Water content0.489 0.797 0.595 0.571 0.581 0.494 Assay - Pantoprazole 98.9 97.2 92.196.5 90.6 92.3 RS Imp A 0.07 0.06 0.07 0.05 0.02 0.06 Imp B ND ND ND NDND 0.01 Imp D&F 0.05 0.06 0.11 0.06 0.10 0.14 Imp E 0.01 0.02 0.01 0.010.01 0.01 SMI 0.03 0.02 0.02 0.02 0.03 0.03 Imp C 0.01 0.00 0.01 0.010.02 0.03 Total (Excluding 0.22 0.26 0.27 0.23 0.32 0.32 Imp C) Analysisof Pantoprazole Composition combined with Liquid Phase Description ClearClear Clear Clear Clear Clear Colorless Colorless Colorless ColorlessColorless Colorless Solution Solution Solution Solution SolutionSolution pH 9.67 9.46 9.56 9.09 8.75 8.95 Osmolality 273 291 294 281 289300 Assay - Pantoprazole NA 102.3 99.1 NA 95.6 100.4 Assay - NaCl 99.0100.4 100.2 99.7 100 99.2 RS Imp A NA ND 0.08 NA NA 0.02 Imp B NA ND NDNA NA ND Imp D&F NA ND 0.15 NA NA 0.05 Imp E NA ND 0.01 NA NA 0.00 SMINA ND 0.05 NA NA 0.01 Imp C NA ND 0.02 NA NA 0.01 Total (Excluding NA ND0.36 NA NA 0.02 Imp C) LPC TEST 10 μm NA Complies Complies NA CompliesComplies 1A 25 μm NA NA

TABLE 4C Stability Testing at 2-8° C. of Pantoprazole Compositionsformed from Bulk Solutions Processed under Various Conditions (cont.)Exemplary Composition 5 Exemplary Composition 6 Bulk SolutionFormulation IB II Blending Process Process I Process II Bulk SolutionTemperature 4° C., with 0.45% NaCl Water and Acetone Condition 1 Month 3Months 1 Month 3 Months Initial 2-8° C. 2-8° C. Initial 2-8° C. 2-8° C.Analysis of Pantoprazole Composition without Liquid Phase DescriptionWhite White White White White White colored colored colored coloredcolored colored powder powder powder powder powder powder Water content0.687 0.842 0.952 NA 0.814 NA Assay - Pantoprazole 97.2 90.2 87.4 100.499.2 NA RS Imp A 0.05 0.05 0.01 0.05 0.05 NA Imp B ND ND 0.01 ND ND NAImp D&F 0.06 0.20 0.13 0.02 0.03 NA Imp E 0.01 0.03 ND 0.01 0.02 NA SMI0.02 0.06 0.03 0.02 0.01 NA Imp C 0.01 0.01 0.02 ND 0.01 NA Total(Excluding 0.19 0.47 0.20 0.16 0.14 NA Imp C) Analysis of PantoprazoleComposition combined with Liquid Phase Description Clear Clear ClearClear Clear Clear Colorless Colorless Colorless Colorless ColorlessColorless Solution Solution Solution Solution Solution Solution pH 9.629.21 9.31 9.36 9.16 9.17 Osmolality 143 144 306 294 277 295 Assay -Pantoprazole NA 94.5 97.44 95.445 94.92 106.1 Assay - NaCl 101.7 100102.6 NA 97.2 100.4 RS Imp A NA NA 0.06 0.06 0.05 0.05 Imp B NA NA 0.00ND ND ND Imp D&F NA NA 0.13 0.03 0.04 0.03 Imp E NA NA 0.01 0.01 0.010.01 SMI NA NA 0.04 0.02 0.03 0.01 Imp C NA NA 0.02 ND 0.02 0.03 Total(Excluding NA NA 0.31 0.21 0.18 0.11 Imp C) LPC TEST 10 μm NA CompliesComplies Complies Complies NA 1A 25 μm NA NA

TABLE 5A Stability Testing at 25° C. and Relative Humidity of 40% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions Exemplary Composition 7 Exemplary Composition 8 BulkSolution Formulation IA IA Blending Process Process I Process I BulkSolution Temperature 25° C. 25° C. Condition 1 Month 3 Months 1 Month 3Months 25° C. 25° C. 25° C. 25° C. Initial 40% Rh 40% Rh Initial 40% Rh40% Rh Analysis of Pantoprazole Composition without Liquid PhaseDescription White White White White White White colored colored coloredcolored colored colored powder powder powder powder powder powder Watercontent 0.500 0.639 0.496 0.555 0.532 0.572 Assay - Pantoprazole 99.298.6 94.5 99.2 97.4 97.44 RS Imp A 0.07 0.08 0.07 0.07 0.08 0.07 Imp BND ND 0.02 ND ND 0.01 Imp D&F 0.06 0.09 0.12 0.06 0.09 0.17 Imp E 0.010.01 0.01 0.01 0.01 0.01 SMI 0.03 0.03 0.05 0.03 0.03 0.06 Imp C 0.010.00 0.02 0.01 0.00 0.02 Total (Excluding 0.24 0.32 0.35 0.24 0.35 0.39Imp C) Analysis of Pantoprazole Composition combined with Liquid PhaseDescription Clear Clear Clear Clear Clear Clear Colorless ColorlessColorless Colorless Colorless Colorless Solution Solution SolutionSolution Solution Solution pH 9.58 9.53 9.42 9.58 9.55 9.4 Osmolality279 289 290 273 282 288 Assay - Pantoprazole Na 93.4 93.8 NA 93.3 94.0Assay - NaCl 99.8 96.5 100.5 99.3 96.7 100.2 RS Imp A NA 0.08 0.04 NA0.07 0.04 Imp B NA ND 0.00 NA ND 0.00 Imp D&F NA 0.13 0.11 NA 0.13 0.11Imp E NA 0.01 0.10 NA 0.01 0.00 SMI NA 0.06 0.03 NA 0.08 0.03 Imp C NA0.02 0.03 NA 0.03 0.02 Total (Excluding NA 0.41 0.22 NA 0.50 0.22 Imp C)LPC TEST 10 μm NA Complies Complies NA Complies Complies 1A 25 μm NA NA

TABLE 5B Stability Testing at 25° C. and Relative Humidity of 40% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions (cont.) Exemplary Composition 9 Exemplary Composition10 Bulk Solution Formulation IA IA Blending Process Process I Process IBulk Solution Temperature 4° C. 4° C., Exposed to 30/65 for 7.30 hrCondition 1 Month 3 Months 1 Month 3 Months 25° C. 25° C. 25° C. 25° C.Initial 40% Rh 40% Rh Initial 40% Rh 40% Rh Analysis of PantoprazoleComposition without Liquid Phase Description White White White WhiteWhite brown colored colored colored colored colored powder powder powderpowder powder powder Water content 0.489 0.516 0.548 0.571 0.519 0.309Assay - Pantoprazole 98.9 97.0 96.1 96.5 95.13 91.56 RS Imp A 0.07 0.08NA 0.05 0.02 0.09 Imp B ND ND 0.07 ND ND 0.06 Imp D&F 0.05 0.06 ND 0.060.09 0.53 Imp E 0.01 0.09 0.17 0.01 0.01 ND SMI 0.03 0.01 0.01 0.02 0.030.08 Imp C 0.01 0.00 0.03 0.01 0.02 0.34 Total (Excluding 0.22 0.32 0.020.23 0.02 1.39 Imp C) Analysis of Pantoprazole Composition combined withLiquid Phase Description Clear Clear Clear Clear Clear Clear ColorlessColorless Colorless Colorless Colorless Colorless Solution SolutionSolution Solution Solution Solution pH 9.67 9.56 8.9 9.09 8.76 9.47Osmolality 273 291 289 281 294 287 Assay - Pantoprazole NA 90.9 92.4 NA91.5 90.8 Assay - NaCl 99.0 94.3 99.8 99.7 98.1 101.8 RS Imp A NA 0.070.08 NA NA 0.06 Imp B NA ND 0.01 NA NA 0.01 Imp D&F NA 0.12 0.21 NA NA0.19 Imp E NA 0.02 0.01 NA NA 0.01 SMI NA 0.06 0.05 NA NA 0.06 Imp C NA0.03 0.02 NA NA 0.13 Total (Excluding NA 0.40 0.45 NA NA 0.51 Imp C) LPCTEST 10 μm NA Complies Complies NA Complies Complies 1A 25 μm NA NA

TABLE 5C Stability Testing at 25° C. and Relative Humidity of 40% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions (cont.) Exemplary Composition 11 ExemplaryComposition 12 Bulk Solution Formulation IB II Blending Process ProcessI Process II Bulk Solution Temperature 4° C., with 0.45% NaCl Water andAcetone Condition 1 Month 3 Months 1 Month 3 Months 25° C. 25° C. 25° C.25° C. Initial 40% Rh 40% Rh Initial 40% Rh 40% Rh Analysis ofPantoprazole Composition without Liquid Phase Description White WhiteWhite White White NA colored colored colored colored colored powderpowder powder powder powder Water content 0.687 1.255 0.804 NA 0.717 NAAssay - Pantoprazole 97.2 95.34 89.145 100.4 99.7 NA RS Imp A 0.05 0.050.06 0.05 0.05 NA Imp B ND ND ND ND ND NA Imp D&F 0.06 0.16 0.18 0.020.05 NA Imp E 0.01 0.02 0.01 0.01 0.02 NA SMI 0.02 0.06 0.02 0.02 0.03NA Imp C 0.01 0.02 0.02 ND 0.02 NA Total (Excluding 0.19 0.44 0.32 0.160.17 NA Imp C) Analysis of Pantoprazole Composition combined with LiquidPhase Description Clear Clear Clear Clear Clear Clear ColorlessColorless Colorless Colorless Colorless Colorless Solution SolutionSolution Solution Solution Solution pH 9.62 9.11 9.18 9.36 9.24 9.21Osmolality 143 144 287 294 282 287 Assay - Pantoprazole NA 90.9 92.090.9 89.6 99.2 Assay - NaCl 101.7 103.6 101.2 NA 98.5 100 RS Imp A NA NA0.06 0.06 0.05 0.05 Imp B NA NA 0.00 ND ND ND Imp D&F NA NA 0.17 0.030.07 0.10 Imp E NA NA 0.01 0.01 0.02 ND SMI NA NA 0.05 0.02 0.03 0.02Imp C NA NA 0.03 ND 0.02 0.06 Total (Excluding NA NA 0.36 0.21 0.19 0.19Imp C) LPC TEST 10 μm NA Complies Complies Complies Complies NA 1A 25 μmNA NA

TABLE 6A Stability Testing at 30° C. and Relative Humidity of 65% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions Exemplary Composition 13 Exemplary Composition 14Bulk Solution Formulation IA IA Blending Process Process I Process IBulk Solution Temperature 25° C. 25° C. Condition 1 Month 3 Months 1Month 3 Months 30° C. 30° C. 30° C. 30° C. Initial 65% Rh 65% Rh Initial65% Rh 65% Rh Analysis of Pantoprazole Composition without Liquid PhaseDescription White White White White White White colored colored coloredcolored colored colored powder powder powder powder powder powder Watercontent 0.500 0.598 0.464 0.555 0.614 0.560 Assay - Pantoprazole 99.297.3 93.7 99.2 95.4 96.4 RS Imp A 0.07 0.09 0.08 0.07 0.09 0.78 Imp B NDND ND ND ND ND Imp D&F 0.06 0.09 0.20 0.06 0.09 0.21 Imp E 0.01 0.010.01 0.01 0.01 0.01 SMI 0.03 0.03 0.04 0.03 0.05 0.04 Imp C 0.01 0.00 ND0.01 0.00 ND Total (Excluding 0.24 0.34 0.39 0.24 0.36 1.09 Imp C)Analysis of Pantoprazole Composition combined with Liquid PhaseDescription Clear Clear Clear Clear Clear Clear Colorless ColorlessColorless Colorless Colorless Colorless Solution Solution SolutionSolution Solution Solution pH 9.58 9.56 9.23 9.58 9.5 9.16 Osmolality279 292 278 273 285 274 Assay - Pantoprazole Na 96.0 95.9 NA 96.5 97.3Assay - NaCl 99.8 97.9 99.2 99.3 98.3 98.4 RS Imp A NA 0.08 0.08 NA 0.080.08 Imp B NA ND ND NA ND ND Imp D&F NA 0.14 0.25 NA 0.14 0.25 Imp E NA0.01 ND NA 0.01 ND SMI NA 0.08 0.06 NA 0.08 0.15 Imp C NA 0.03 0.05 NA0.03 0.05 Total (Excluding NA 0.50 0.46 NA 0.43 0.61 Imp C) LPC TEST 10μm NA Complies Complies NA Complies Complies 1A 25 μm NA NA

TABLE 6B Stability Testing at 30° C. and Relative Humidity of 65% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions (cont.) Exemplary Composition 15 ExemplaryComposition 16 Bulk Solution Formulation IA IA Blending Process ProcessI Process I Bulk Solution Temperature 4° C. 4° C., Exposed to 30/65 for7.30 hr Condition 1 Month 3 Months 1 Month 3 Months 30° C. 30° C. 30° C.30° C. Initial 65% Rh 65% Rh Initial 65% Rh 65% Rh Analysis ofPantoprazole Composition without Liquid Phase Description White WhiteWhite White White Brown colored colored colored colored colored coloredpowder powder powder powder powder crystal powder Water content 0.4890.555 0.537 0.571 0.553 6.350 Assay - Pantoprazole 98.9 110.8 93.2 96.589.7 76.4 RS Imp A 0.07 0.07 0.16 0.05 0.20 0.16 Imp B ND ND ND ND ND0.18 Imp D&F 0.05 0.11 0.41 0.06 0.14 1.43 Imp E 0.01 0.02 ND 0.01 ND NDSMI 0.03 0.03 0.08 0.02 0.02 0.33 Imp C 0.01 0.00 ND 0.01 0.02 0.50Total (Excluding 0.22 0.36 0.78 0.23 0.24 2.86 Imp C) Analysis ofPantoprazole Composition combined with Liquid Phase Description ClearClear Clear Clear Clear Clear Colorless Colorless Colorless ColorlessColorless Colorless Solution Solution Solution Solution SolutionSolution pH 9.67 9.54 9.2 9.09 8.82 9.26 Osmolality 273 290 280 281 288280 Assay - Pantoprazole NA 94.8 95.8 NA 88.8 93.9 Assay - NaCl 99.098.8 103.6 99.7 98.2 97.6 RS Imp A NA 0.07 0.08 NA NA 0.07 Imp B NA NDND NA NA ND Imp D&F NA 0.13 0.25 NA NA 0.24 Imp E NA 0.01 0.02 NA NA NDSMI NA 0.07 0.06 NA NA 0.05 Imp C NA 0.03 0.06 NA NA 0.12 Total(Excluding NA 0.44 0.46 NA NA 0.45 Imp C) LPC TEST 10 μm NA CompliesComplies NA Complies Complies 1A 25 μm NA NA

TABLE 6C Stability Testing at 30° C. and Relative Humidity of 65% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions (cont.) Exemplary Composition 17 ExemplaryComposition 18 Bulk Solution Formulation IB II Blending Process ProcessI Process II Bulk Solution Temperature 4° C. with 0.45% NaCl Water andAcetone Condition 1 Month 3 Months 1 Month 3 Months 30° C. 30° C. 30° C.30° C. Initial 65% Rh 65% Rh Initial 65% Rh 65% Rh Analysis ofPantoprazole Composition without Liquid Phase Description White WhiteWhite White White White colored colored colored colored colored coloredpowder powder powder powder powder powder Water content 0.687 0.9580.876 NA 0.698 NA Assay - Pantoprazole 97.2 89.6 94.4 100.4 99.5 NA RSImp A 0.05 0.05 0.06 0.05 0.06 NA Imp B ND ND ND ND ND NA Imp D&F 0.060.18 0.24 0.02 0.05 NA Imp E 0.01 0.02 ND 0.01 0.02 NA SMI 0.02 0.060.03 0.02 0.02 NA Imp C 0.01 0.03 ND ND 0.01 NA Total (Excluding 0.190.48 0.41 0.16 0.19 NA Imp C) Analysis of Pantoprazole Compositioncombined with Liquid Phase Description Clear Clear Clear Clear ClearClear Colorless Colorless Colorless Colorless Colorless ColorlessSolution Solution Solution Solution Solution Solution pH 9.62 9.13 9.179.36 9.39 9.32 Osmolality 143 151 141 294 285 292 Assay - PantoprazoleNA 88.8 93.1 90.9 91.7 98 Assay - NaCl 101.7 98.2 91 NA 98.4 99.6 RS ImpA NA NA 0.06 0.06 0.05 0.05 Imp B NA NA NA ND ND ND Imp D&F NA NA 0.220.03 0.08 0.12 Imp E NA NA NA 0.01 0.02 ND SMI NA NA 0.06 0.02 0.03 0.02Imp C NA NA 0.06 ND 0.06 0.06 Total (Excluding NA NA 0.39 0.21 0.25 0.21Imp C) LPC TEST 10 μm NA Complies Complies Complies Complies NA 1A 25 μmNA NA

TABLE 7A Stability Testing at 40° C. and Relative Humidity of 15% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions Exemplary Composition 19 Exemplary Composition 20Bulk Solution Formulation IA IA Blending Process Process I Process IBulk Solution Temperature 25° C. 25° C. Condition 1 Month 3 Months 1Month 3 Months 40° C. 40° C. 40° C. 40° C. Initial 15% Rh 15% Rh Initial15% Rh 15% Rh Analysis of Pantoprazole Composition without Liquid PhaseDescription White White White White White White colored colored coloredcolored colored colored powder powder powder powder powder powder Watercontent 0.500 0.688 0.523 0.555 0.534 0.522 Assay - Pantoprazole 99.296.4 93.9 99.2 98.5 88.4 RS Imp A 0.07 0.07 0.08 0.07 0.07 0.10 Imp B NDND ND ND ND 0.02 Imp D&F 0.06 0.10 0.20 0.06 0.14 0.43 Imp E 0.01 0.010.01 0.01 0.01 ND SMI 0.03 0.04 0.05 0.03 0.04 0.08 Imp C 0.01 0.00 ND0.01 0.00 ND Total (Excluding 0.24 0.35 0.52 0.24 0.43 0.82 Imp C)Analysis of Pantoprazole Composition combined with Liquid PhaseDescription Clear Clear Clear Clear Clear Clear Colorless ColorlessColorless Colorless Colorless Colorless Solution Solution SolutionSolution Solution Solution pH 9.58 9.54 9.26 9.58 9.57 9.2 Osmolality279 294 275 273 286 278 Assay - Pantoprazole Na 91.9 99.8 NA 93.5 96Assay - NaCl 99.8 94.1 96.5 99.3 97.1 101.4 RS Imp A NA 0.04 0.09 NA0.10 0.10 Imp B NA ND 0.02 NA ND 0.03 Imp D&F NA 0.10 0.40 NA 0.28 0.51Imp E NA ND NA NA 0.01 NA SMI NA 0.05 0.09 NA 0.08 0.11 Imp C NA 0.02 NANA 0.06 0.04 Total (Excluding NA 0.27 0.73 NA 0.73 0.94 Imp C) LPC TEST10 μm NA Complies NA NA Complies Complies 1A 25 μm NA NA NA

TABLE 7B Stability Testing at 40° C. and Relative Humidity of 15% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions (cont.) Exemplary Composition 21 ExemplaryComposition 22 Bulk Solution Formulation IA IA Blending Process ProcessI Process I Bulk Solution Temperature 4° C. 4° C., Exposed to 30/65 for7.30 hr Condition 1 Month 3 Months 1 Month 3 Months 40° C. 40° C. 40° C.40° C. Initial 15% Rh 15% Rh Initial 15% Rh 15% Rh Analysis ofPantoprazole Composition without Liquid Phase Description White WhiteWhite White White Off White colored colored colored colored coloredPowder powder powder powder powder powder Water content 0.489 0.5690.623 0.571 0.507 0.506 Assay - Pantoprazole 98.9 96.7 90.6 96.5 85.987.0 RS Imp A 0.07 0.07 0.22 0.05 0.04 0.22 Imp B ND ND 0.04 ND ND 0.14Imp D&F 0.05 0.15 0.98 0.06 0.31 2.21 Imp E 0.01 0.01 ND 0.01 0.01 NDSMI 0.03 0.04 0.13 0.02 0.05 0.32 Imp C 0.01 0.00 ND 0.01 0.08 0.96Total (Excluding 0.22 0.44 1.71 0.23 0.65 3.42 Imp C) Analysis ofPantoprazole Composition combined with Liquid Phase Description ClearClear Clear Clear Clear Clear Colorless Colorless Colorless ColorlessColorless Colorless Solution Solution Solution Solution SolutionSolution pH 9.67 9.53 9.19 9.09 8.8 9.07 Osmolality 273 289 279 281 289274 Assay - Pantoprazole NA 92.6 96.3 NA 89.6 86.1 Assay - NaCl 99.098.0 103.8 99.7 98.4 99.1 RS Imp A NA 0.08 0.06 NA NA 0.06 Imp B NA ND0.01 NA NA 0.04 Imp D&F NA 0.23 0.31 NA NA 0.68 Imp E NA 0.02 NA NA NANA SMI NA 0.09 0.06 NA NA 0.43 Imp C NA 0.04 0.02 NA NA 1.25 Total(Excluding NA 0.61 0.60 NA NA 2.02 Imp C) LPC TEST 10 μm NA CompliesComplies NA Complies Complies 1A 25 μm NA NA

TABLE 7C Stability Testing at 40° C. and Relative Humidity of 15% ofPantoprazole Compositions formed from Bulk Solutions Processed underVarious Conditions (cont.) Exemplary Composition 23 ExemplaryComposition 24 Bulk Solution Formulation IB II Blending Process ProcessI Process II Bulk Solution Temperature 4° C., with 0.45% NaCl Water andAcetone Condition 1 Month 3 Months 1 Month 3 Months 40° C. 40° C. 40° C.40° C. Initial 15% Rh 15% Rh Initial 15% Rh 15% Rh Analysis ofPantoprazole Composition without Liquid Phase Description White WhiteWhite White White Off-White colored colored colored colored coloredColored powder powder powder powder powder powder Water content 0.6870.858 0.845 NA 0.788 NA Assay - Pantoprazole 97.2 86.3 91.7 100.4 98.5NA RS Imp A 0.05 0.05 0.09 0.05 0.07 NA Imp B ND ND 0.01 ND ND NA ImpD&F 0.06 0.16 0.49 0.02 0.25 NA Imp E 0.01 0.02 ND 0.01 0.02 NA SMI 0.020.03 0.05 0.02 0.04 NA Imp C 0.01 0.02 0.04 ND 0.01 NA Total (Excluding0.19 0.37 0.79 0.16 0.52 NA Imp C) Analysis of Pantoprazole Compositioncombined with Liquid Phase Description Clear Clear Clear Clear ClearYellowish Colorless Colorless Colorless Colorless Colorless ClearSolution Solution Solution Solution Solution Solution pH 9.62 9.17 9.119.36 9.41 9.39 Osmolality 143 148 428 294 291 286 Assay - PantoprazoleNA 89.4 95.1 90.9 92.5 95.2 Assay - NaCl 101.7 99.5 296 NA 98.6 101.2 RSImp A NA NA 0.09 0.06 0.08 0.16 Imp B NA NA NA ND ND 0.05 Imp D&F NA NA0.51 0.03 0.40 0.89 Imp E NA NA NA 0.01 0.01 0.01 SMI NA NA 0.07 0.020.05 0.08 Imp C NA NA 0.11 ND 0.23 0.51 Total (Excluding NA NA 0.91 0.210.77 1.62 Imp C) LPC TEST 10 μm NA Complies Complies Complies CompliesNA 1A 25 μm NA NA

As used herein, and unless the context dictates otherwise, the term“coupled to” is intended to include both direct coupling (in which twoelements that are coupled to each other contact each other) and indirectcoupling (in which at least one additional element is located betweenthe two elements). Therefore, the terms “coupled to” and “coupled with”are used synonymously.

In some embodiments, the numbers expressing quantities of ingredients,properties such as concentration, reaction conditions, and so forth,used to describe and claim certain embodiments of the invention are tobe understood as being modified in some instances by the term “about.”Accordingly, in some embodiments, the numerical parameters set forth inthe written description and attached claims are approximations that canvary depending upon the desired properties sought to be obtained by aparticular embodiment. In some embodiments, the numerical parametersshould be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and parameters setting forth the broad scopeof some embodiments of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspracticable. The numerical values presented in some embodiments of theinvention may contain certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

Unless the context dictates the contrary, all ranges set forth hereinshould be interpreted as being inclusive of their endpoints andopen-ended ranges should be interpreted to include only commerciallypractical values. Similarly, all lists of values should be considered asinclusive of intermediate values unless the context indicates thecontrary.

As used in the description herein and throughout the claims that follow,the meaning of “a,” “an,” and “the” includes plural reference unless thecontext clearly dictates otherwise. Also, as used in the descriptionherein, the meaning of “in” includes “in” and “on” unless the contextclearly dictates otherwise.

The recitation of ranges of values herein is merely intended to serve asa shorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value with a range is incorporated into the specification asif it were individually recited herein. All methods described herein canbe performed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided with respectto certain embodiments herein is intended merely to better illuminatethe invention and does not pose a limitation on the scope of theinvention otherwise claimed. No language in the specification should beconstrued as indicating any non-claimed element essential to thepractice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember can be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. One ormore members of a group can be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is herein deemed to contain the groupas modified thus fulfilling the written description of all Markushgroups used in the appended claims.

It should be apparent to those skilled in the art that many moremodifications besides those already described are possible withoutdeparting from the inventive concepts herein. The inventive subjectmatter, therefore, is not to be restricted except in the spirit of theappended claims. Moreover, in interpreting both the specification andthe claims, all terms should be interpreted in the broadest possiblemanner consistent with the context. In particular, the terms “comprises”and “comprising” should be interpreted as referring to elements,components, or steps in a non-exclusive manner, indicating that thereferenced elements, components, or steps may be present, or utilized,or combined with other elements, components, or steps that are notexpressly referenced. Where the specification claims refers to at leastone of something selected from the group consisting of A, B, C . . . andN, the text should be interpreted as requiring only one element from thegroup, not A plus N, or B plus N, etc.

What is claimed is:
 1. A spray-dried storage stable pantoprazolecomposition comprising: pantoprazole; and an excipient matrix comprisingsodium chloride (NaCl); wherein the pantoprazole is substantiallyuniformly dispersed in the excipient matrix.
 2. The storage stablepantoprazole composition of claim 1, wherein the pantoprazole-is in formof pantoprazole sodium sesquihydrate.
 3. The storage stable pantoprazolecomposition of claim 1, wherein the pantoprazole and the sodium chlorideare present in a weight ratio of from about 1:100 to about 1:1.
 4. Thestorage stable pantoprazole composition of claim 1, wherein theexcipient further comprises a salt other than sodium chloride, an aminoacid, a sugar, or combinations thereof.
 5. The storage stablepantoprazole composition of claim 1, wherein the composition, afterstorage at 25° C. and 40% relative humidity for 12 weeks, contains equalor less than 0.20% by weight of a pantoprazole sulfone degradant basedon a total weight of the composition.
 6. A kit comprising: a. a storagestable pantoprazole composition according to claim 1; b. a liquid phase;and c. a container that separately contains the pantoprazole compositionand the liquid phase.
 7. The kit of claim 6, wherein the containercomprises a first pouch and wherein the storage stable pantoprazolecomposition is contained in a first chamber of the first pouchcomprising a polymeric material.
 8. The kit of claim 7, wherein thecontainer comprises a second pouch and wherein the liquid phase iscontained is contained in a second chamber of the second pouchcomprising a polymeric material, wherein the first pouch and the secondpouch are coupled together, and wherein the first chamber and the secondchamber are fluidly isolated from each other.
 9. The kit of claim 6,wherein the storage stable pantoprazole composition is present in anamount of from about 20 to about 100 mg.
 10. The kit of claim 6, whereinthe liquid phase comprises water.
 11. The kit of claim 6, wherein theliquid phase is present in an amount of from about 10 to about 200 mL.12. A method for forming a storage stable pantoprazole composition,comprising: combining a bulking agent and water to form a firstsolution; combining pantoprazole and the first solution to form a secondsolution; combining sodium hydroxide and the second solution to form abulk solution; and removing water from the bulk solution by a spray-dryprocess to form the storage stable pantoprazole composition.
 13. Themethod of claim 12, wherein the spray dry process comprisesspray-drying, spray solidification, or spray pilling.
 14. The method ofclaim 12, wherein the bulking agent comprises a salt, an amino acid, asugar, or combinations thereof.
 15. The method of claim 14, wherein: a.the salt comprises sodium chloride (NaCl), magnesium chloride (MgCl₂),calcium chloride (CaCl₂), or combinations thereof; b. the amino acidcomprises glycine; c. the sugar comprises dextrose, sucrose, trehalose,or combinations thereof; or d. any combination of a. through c.
 16. Themethod of claim 12, wherein the sodium hydroxide is combined with thesecond solution in an amount sufficient for the bulk solution to have apH of from about 8 to about
 10. 17. The method of claim 12, wherein thestep of combining the sodium hydroxide and the second solution isfurther defined as forming a third solution, and wherein the methodfurther comprises combining a solvent and the third solution to form thebulk solution.
 18. The method of claim 17, wherein the solvent comprisesacetone.
 19. The method of claim 12, wherein the water combined with thebulking agent has a temperature of from about 1° C. to about 10° C. 20.The method of claim 12, wherein the water combined with the bulkingagent has a temperature of from about 15° C. to about 30° C.